Implantable neurostimulator for providing electrical stimulation of cervical vagus nerves for treatment of chronic cardiac dysfunction with bounded titration

ABSTRACT

A system for providing electrical stimulation of cervical vagus nerves for treatment of chronic cardiac dysfunction with bounded titration is provided. The system includes a patient-operable external controller to transmit a plurality of unique signals. The system further includes an implantable neurostimulator, which includes a pulse generator to deliver electrical therapeutic stimulation tuned to restore autonomic balance through continuously-cycling, intermittent and periodic electrical pulses that result in creation and propagation (in both afferent and efferent directions) of action potentials within the cervical vagus nerve of a patient through a pair of helical electrodes via an electrically coupled nerve stimulation therapy lead. The neurostimulator also includes a recordable memory storing an autotitration operating mode that includes a maximum stimulation intensity and is configured to increase an intensity of the delivered electrical therapeutic stimulation up to a level not exceeding the maximum stimulation intensity upon receipt of one of the unique signals.

CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application is a continuation of U.S. patent applicationSer. No. 14/179,813, filed Feb. 13, 2014 which is a divisional of U.S.patent application Ser. No. 13/931,961, filed Jun. 30, 2013, now U.S.Pat. No. 8,700,150 issued Apr. 15, 2014, which is a continuation-in-partof U.S. patent application Ser. No. 13/352,244, filed Jan. 17, 2012, nowU.S. Pat. No. 8,571,654 issued Oct. 29, 2013, the disclosures of whichare incorporated by reference in their entireties.

FIELD

This application relates in general to chronic cardiac dysfunctiontherapy and, in particular, to an implantable neurostimulator forproviding electrical stimulation of cervical vagus nerves for treatmentof chronic cardiac dysfunction with bounded titration.

BACKGROUND

Vagal nerve stimulation (VNS), therapeutic electrical stimulation of apatient's cervical vagus nerve, is used for treatment of multiple healthconditions, including clinical treatment of drug-refractory epilepsy anddepression. VNS has also been proposed for therapeutic treatment ofheart conditions such as Congestive Heart Failure (CHF), a chronicmedical condition in which the heart is unable to pump sufficient bloodto meet the body's needs. For instance, VNS has been demonstrated incanine studies as efficacious in simulated treatment of atrialfibrillation (AF) and heart failure, such as described in Zhang et al.,“Therapeutic Effects of Selective Atrioventricular Node VagalStimulation in Atrial Fibrillation and Heart Failure,” J. Cardiovasc.Electrophysiol., Vol. 24, pp. 86-91 (January 2013), the disclosure ofwhich is incorporated by reference.

VNS therapy commonly requires an implantation of a neurostimulator, asurgery requiring several weeks of recovery before a patient can startreceiving VNS therapy. Even after the recovery, the neurostimulator doesnot immediately start delivering a full therapeutic dose of VNS to avoidcausing significant patient discomfort and other undesirable sideeffects. Instead, to allow the patient to adjust to the VNS therapy, theintensity is gradually up titrated over a period of time under a controlof a physician. Medically, such a titration can be completed in a periodnot exceeding two months. The titration can take significantly longer inpractice because the increase in intensity must generally be performedby a physician or another healthcare professional. Thus, for every stepin the titration to take place, the patient has to visit the physician'soffice. These visits generally occur once every one to three months dueto scheduling conflicts, and can extend the titration process to as muchas a year, during which the patient in need of VNS does not receive theVNS at the full therapeutic intensity.

The medically unnecessary delays in delivering therapeutic levels of VNScan further accumulate if the therapy is disrupted following the initialtitration, such as if the implanted VNS neurostimulator runs out ofpower. Power for a conventional VNS neurostimulator is typicallyprovided by an onboard battery. Delivering therapeutic VNS through animplantable neurostimulator presents battery longevity concerns similarto other types of implantable pulse generators, although a VNSneurostimulator is therapeutic and non-life sustaining Still, as theduty cycle of a VNS neurostimulator can at times be near constant,battery depletion can occur at a faster rate than with cardiacpacemakers, implantable cardioverter defibrillators (ICDs) and similarimplantable devices that are triggered relatively infrequently undernormal conditions. The in-service lifetime of a conventional VNSneurostimulator typically varies from three to seven years, dependingupon programming, particularly duty cycle and stimulation intensity. Aswell, an increase in lead impedance can further cause premature batterydepletion. Battery depletion necessitates eventual neurostimulatorexplantation and replacement, with attendant surgical risks of injuryand infection. The disruption in therapy caused by the surgery requiresa new cycle of titration of therapeutic intensity, which as describedabove, can take up to a year. Thus, a patient using a conventional VNSstimulator can be subjected to repeated, prolonged, and medicallyunjustified delays in receiving VNS stimulation that can be harmful tothe patient's health.

In addition to the challenges associated with conventional VNSstimulators described above, conventional VNS stimulators do not achieveoptimum effectiveness in treating the underlying causes of CHF. CHF, aswell as other forms of chronic cardiac dysfunction, are generallyattributed to an autonomic imbalance of the sympathetic andparasympathetic nervous systems that, if left untreated, can lead tocardiac arrhythmogenesis, progressively worsening cardiac function andeventual patient death. Furthermore, CHF is pathologically characterizedby an elevated neuroexitatory state and is accompanied by physiologicalindications of impaired arterial and cardiopulmonary baroreflex functionwith reduced vagal activity.

Experimental VNS for cardiac therapy has focused on the efferent nervesof the parasympathetic nervous system, such as described in Sabbah etal., “Vagus Nerve Stimulation in Experimental Heart Failure,” HeartFail. Rev., 16:171-178 (2011), the disclosure of which is incorporatedby reference. Sabbah discusses canine studies using a VNS systemmanufactured by BioControl Medical Ltd., Yehud, Israel, that includes anelectrical pulse generator, right ventricular endocardial sensing lead,and right vagus nerve cuff stimulation lead. The sensing lead enablesclosed loop synchronization to the cardiac cycle; stimulation isdelivered only when heart rate increases above a preset threshold. Anasymmetric tri-polar nerve cuff electrode provides cathodic induction ofaction potentials while simultaneously applying asymmetric anodal blocksthat lead to preferential activation of vagal efferent fibers.Stimulation is provided at an intensity and frequency intended tomeasurably reduce basal heart rate by ten percent by preferentialstimulation of efferent vagus nerve fibers leading to the heart whileblocking afferent neural impulses to the brain. The degree oftherapeutic effect on parasympathetic activation occurs throughincidental recruitment of afferent parasympathetic nerve fibers in thevagus, as well as through recruitment of efferent fibers.

Other uses of electrical nerve stimulation for therapeutic treatment ofcardiac and physiological conditions are described. For instance, U.S.Pat. No. 8,219,188, issued Jul. 10, 2012 to Craig disclosessynchronization of vagus nerve stimulation with a physiological cycle,such as the cardiac or respiratory cycle, of a patient. Electricalstimulation is applied to the vagus nerve at a selected point in thephysiological cycle correlated with increased afferent conduction, suchas a point from about 10 msec to about 800 msec after an R-wave of thepatient's ECG, optionally during inspiration by the patient; to increaseheart rate variability, such as a point from about 10 msec to about 800msec after an R-wave of the patient's ECG, optionally during expirationby the patient; not correlated with increased efferent conduction on thevagus nerve; to generate efferent electrical activity on the vagusnerve; or upon the detection of a symptom of a medical condition. In afurther embodiment, conventional VNS is applied to the vagus nerve alongwith microburst electrical signals, which is a portion of a therapeuticelectrical signal having a limited plurality of pulses, separated fromone another by interpulse intervals, and a limited burst duration,separated from one another by interburst periods. Stimulation may beapplied to generate efferent electrical activity on the nerve in adirection away from the central nervous system; through a “blocking”type of electrical signal, such that both afferent and efferentelectrical activity on the nerve is prevented from traveling further; orwherein afferent fibers are stimulated while efferent fibers are notstimulated or are blocked, and vice versa. By applying a series ofmicrobursts to the vagus nerve, enhanced vagal evoked potentials (eVEP)are produced in therapeutically significant areas of the brain, incontrast to conventional VNS alone, which fails to produce eVEP.

U.S. Pat. No. 6,600,954, issued Jul. 29, 2003 to Cohen et al. disclosesa method and apparatus for selective control of nerve fiber activationsfor reducing pain sensations in the legs and arms. An electrode deviceis applied to a nerve bundle capable of generating, upon activation,unidirectional action potentials that propagate through both smalldiameter and large diameter sensory fibers in the nerve bundle, and awayfrom the central nervous system.

U.S. Pat. No. 6,684,105, issued Jan. 27, 2004 to Cohen et al. disclosesan apparatus for treatment of disorders by unidirectional nervestimulation. An apparatus for treating a specific condition includes aset of one or more electrode devices that are applied to selected sitesof the central or peripheral nervous system of the patient. For someapplications, a signal is applied to a nerve, such as the vagus nerve,to stimulate efferent fibers and treat motility disorders, or to aportion of the vagus nerve innervating the stomach to produce asensation of satiety or hunger. For other applications, a signal isapplied to the vagus nerve to modulate electrical activity in the brainand rouse a comatose patient, or to treat epilepsy and involuntarymovement disorders.

U.S. Pat. No. 7,123,961, issued Oct. 17, 2006 to Kroll et al. disclosesstimulation of autonomic nerves. An autonomic nerve is stimulated toaffect cardiac function using a stimulation device in electricalcommunication with the heart by way of three leads suitable fordelivering multi-chamber stimulation and shock therapy. For arrhythmiadetection, the device utilizes atrial and ventricular sensing circuitsto sense cardiac signals to determine whether a rhythm is physiologic orpathologic. The timing intervals between sensed events are classified bycomparing them to a predefined rate zone limit and other characteristicsto determine the type of remedial therapy needed, which includesbradycardia pacing, anti-tachycardia pacing, cardioversion shocks(synchronized with an R-wave), or defibrillation shocks (deliveredasynchronously).

U.S. Pat. No. 7,225,017, issued May 29, 2007 to Shelchuk disclosesterminating ventricular tachycardia in connection with any stimulationdevice that is configured or configurable to stimulate nerves, orstimulate and shock a patient's heart. Parasympathetic stimulation isused to augment anti-tachycardia pacing, cardioversion, ordefibrillation therapy. To sense atrial or ventricular cardiac signalsand provide chamber pacing therapy, particularly on the left side of theheart, the stimulation device is coupled to a lead designed forplacement in the coronary sinus or its tributary veins. Cardioversionstimulation is delivered to a parasympathetic pathway upon detecting aventricular tachycardia. A stimulation pulse is delivered via the leadto electrodes positioned proximate to the parasympathetic pathwayaccording to stimulation pulse parameters based at least in part on theprobability of reinitiation of an arrhythmia.

U.S. Pat. No. 7,277,761, issued Oct. 2, 2007 to Shelchuk discloses vagalstimulation for improving cardiac function in heart failure patients. Anautonomic nerve is stimulated to affect cardiac function by way of threeleads suitable for delivering multi-chamber endocardial stimulation andshock therapy. When the stimulation device is intended to operate as animplantable cardioverter-defibrillator (ICD), the device detects theoccurrence of an arrhythmia, and applies a therapy to the heart aimed atterminating the detected arrhythmia. Defibrillation shocks are generallyof moderate to high energy level, delivered asynchronously, andpertaining exclusively to the treatment of fibrillation.

U.S. Pat. No. 7,295,881, issued Nov. 13, 2007 to Cohen et al. disclosesnerve branch-specific action potential activation, inhibition andmonitoring. Two preferably unidirectional electrode configurations flanka nerve junction from which a preselected nerve branch issues withrespect to the brain. Selective nerve branch stimulation can be used inconjunction with nerve-branch specific stimulation to achieve selectivestimulation of a specific range of fiber diameters, substantiallyrestricted to a preselected nerve branch, including heart rate control,where activating only the vagal B nerve fibers in the heart, and notvagal A nerve fibers that innervate other muscles, can be desirous.

U.S. Pat. No. 7,778,703, issued Aug. 17, 2010 to Gross et al. disclosesselective nerve fiber stimulation for treating heart conditions. Anelectrode device is coupled to a vagus nerve and a control unit appliesstimulating and inhibiting currents to the vagus nerve, which arecapable of respectively inducing action potentials in a therapeuticdirection in first and second sets of nerve fibers in the vagus nerveand inhibiting action potentials in the therapeutic direction in thesecond set of nerve fibers only. The nerve fibers in the second set havelarger diameters than the first set's nerve fibers. Typically, thesystem is configured to treat heart failure or heart arrhythmia, such asAF or tachycardia by slowing or stabilizing the heart rate, or reducingcardiac contractility.

U.S. Pat. No. 7,813,805, issued Oct. 12, 2010 to Farazi and U.S. Pat.No. 7,869,869, issued Jan. 11, 2011 to Farazi both disclose subcardiacthreshold vagus nerve stimulation. A vagus nerve stimulator isconfigured to generate electrical pulses below a cardiac threshold,which are transmitted to a vagus nerve, so as to inhibit or reduceinjury resulting from ischemia. For arrhythmia detection, a heartstimulator utilizes atrial and ventricular sensing circuits to sensecardiac signals to determine whether a rhythm is physiologic orpathologic. In low-energy cardioversion, an ICD device typicallydelivers a cardioversion stimulus synchronously with a QRS complex. Ifanti-tachycardia pacing or cardioversion fails to terminate atachycardia, after a programmed time interval or if the tachycardiaaccelerates, the ICD device initiates defibrillation.

U.S. Patent App. Pub. No. 2010/0331908, filed Sep. 10, 2010 by Farazidiscloses subcardiac threshold vagus nerve stimulation in which a vagalnerve stimulator generates electrical pulses below a cardiac thresholdof the heart for treating an ischemia of the heart, or for reducing adefibrillation threshold of the heart. The cardiac threshold is athreshold for energy delivered to the heart above which there is aslowing of the heart rate or the conduction velocity. In operation, thevagal nerve stimulator generates the electrical pulses below the cardiacthreshold, that is, subcardiac threshold electrical pulses, such thatthe beat rate of the heart is not affected. Although the function of thevagal nerve stimulator is to treat an ischemia, or to reduce adefibrillation threshold of the heart, in other embodiments, the vagalnerve stimulator may function to treat heart failure, reduce aninflammatory response during a medical procedure, stimulate the releaseof insulin for treating diabetes, suppress insulin resistance fortreating diabetes, or treat an infarction of the heart.

U.S. Pat. No. 7,634,317, issued Dec. 15, 2009, to Ben-David et al.discloses techniques for applying, calibrating and controlling nervefiber stimulation, which includes a vagal stimulation system comprisinga multipolar electrode device that is applied to a portion of a vagusnerve (a left vagus nerve and/or right vagus nerve), which innervates aheart of a subject. Alternatively, the electrode device is applied to anepicardial fat pad, a pulmonary vein, a carotid artery, a carotid sinus,a coronary sinus, a vena cava vein, a right ventricle, or a jugularvein. The system is utilized for treating a heart condition such asheart failure and/or cardiac arrhythmia; the vagal stimulation systemfurther comprises an implantable or external control unit, whichtypically communicates with electrode device over a set of leads.Typically, the control unit drives the electrode device to (i) applysignals to induce the propagation of efferent nerve impulses towardsheart, and (ii) suppress artificially-induced afferent nerve impulsestowards a brain of the subject, to minimize unintended side effects ofthe signal application; the efferent nerve pulses in vagus nerve aretypically induced by the electrode device to regulate the heart rate ofthe subject.

Finally, U.S. Pat. No. 7,885,709, issued Feb. 8, 2011 to Ben-Daviddiscloses nerve stimulation for treating disorders. An electrode devicestimulates the vagus nerve, so as to modify heart rate variability, orto reduce heart rate, by suppressing the adrenergic (sympathetic)system. Typically, the system is configured to treat heart failure orheart arrhythmia. Therapeutic effects of reduction in heart ratevariability include the narrowing of the heart rate range, therebyeliminating very slow heart rates and very fast heart rates. For thistherapeutic application, the control unit is typically configured toreduce low-frequency heart rate variability, and to adjust the level ofstimulation applied based on the circadian and activity cycles of thesubject. Therapeutic effects also include maximizing the mechanicalefficiency of the heart by maintaining relatively constant ventricularfilling times and pressures.

Notwithstanding, a need remains for an approach to therapeuticallytreating chronic cardiac dysfunction through a neurostimulator thatallows to avoid medically unjustified delays in VNS therapy associatedwith titration of intensity of VNS stimulation.

SUMMARY

Excessive sustained activation of the sympathetic nervous system has adeleterious effect on long term cardiac performance and on the qualityof life and survival of patients suffering from chronic cardiacdysfunction. CHF patients are at increased risk of atrialtachyarrhythmias, such as AF and atrial flutter, and ventriculartachyarrhythmias, such as ventricular tachycardia (VT) and ventricularfibrillation (VF)), particularly when the underlying morbidity is a formof coronary artery disease, cardiomyopathy, mitral valve prolapse, orother valvular heart disease. Low intensity peripheral neurostimulationtherapies that target the imbalance of the autonomic nervous system havebeen shown to improve clinical outcomes. Thus, bi-directional autonomicregulation therapy is delivered to the cervical vagus nerve at anintensity that is insufficient to elicit pathological or acutephysiological side effects and without the requirement of an enablingphysiological feature or triggering physiological marker. Letting apatient in need of such therapy to control the therapy titrationfollowing the implantation of a VNS neurostimulator allows the patientto receive VNS stimulation at a full therapeutic intensity sooner thanif the titration is performed entirely under a control of a healthcareprofessional. Furthermore, placing physician-defined boundaries on thetitration mitigates the risks associated with over-aggressive patienttitration of the stimulation.

One embodiment provides a system for providing electrical stimulation ofcervical vagus nerves for treatment of chronic cardiac dysfunction withbounded titration. The system includes a patient-operable externalcontroller configured to transmit a plurality of unique signalsincluding a unique signal associated with an up-titration command. Thesystem further includes an implantable neurostimulator. The implantableneurostimulator includes a pulse generator configured to deliverelectrical therapeutic stimulation tuned to restore autonomic balancethrough continuously-cycling, intermittent and periodic electricalpulses simultaneously delivered at an intensity that avoids acutephysiological side effects and with an unchanging cycle not triggered byphysiological markers in a manner that results in creation andpropagation (in both afferent and efferent directions) of actionpotentials within neuronal fibers comprising a cervical vagus nerve of apatient through a pair of helical electrodes via an electrically couplednerve stimulation therapy lead. The implantable neurostimulator alsoincludes a recordable memory storing an autotitration operating modethat includes a maximum stimulation intensity and is configured toincrease an intensity of the delivered electrical therapeuticstimulation up to a level not exceeding the maximum stimulationintensity upon receipt of the unique signal associated with theup-titration command.

A further embodiment provides an implantable neurostimulator-implementedmethod for providing electrical stimulation of cervical vagus nerves fortreatment of chronic cardiac dysfunction with bounded titration. Animplantable neurostimulator that includes a pulse generator configuredto deliver electrical therapeutic stimulation in a manner that resultsin creation and propagation (simultaneously in both afferent andefferent directions) of action potentials within neuronal fiberscomprising the cervical vagus nerve of a patient is provided. Anautotitration operating mode is stored into a recordable memory, whichincludes: parametrically defining a maximum stimulation intensity of theelectrical therapeutic stimulation deliverable under the autotitrationoperating mode; and parametrically defining a titration dose of theelectrical therapeutic stimulation tuned to restore cardiac autonomousbalance through continuously-cycling, intermittent and periodicelectrical pulses at an intensity not exceeding the maximum stimulationintensity that avoids acute physiological side affects and with anunchanging cycle not triggered by physiological markers. The titrationdose is therapeutically delivered to the vagus nerve independent ofcardiac cycle via the pulse generator in the implantable neurostimulatorthrough at least a pair of helical electrodes electrically coupled tothe pulse generator via a nerve stimulation therapy lead. Upon receivinga remotely applied signal uniquely associated with an up-titrationcommand from a patient-operable external controller, the titration doseintensity is increased to a level not exceeding the maximum stimulationintensity.

A still further embodiment provides a system for providing a boundedtitration of electrical stimulation of cervical vagus nerves fortreatment of chronic cardiac dysfunction following the stimulation startor disruption. The system includes a patient-operable externalcontroller configured to transmit a unique signal associated with anup-titration command. The system further includes an implantableneurostimulator powered by a rechargeable battery in included in theneurostimulator. The neurostimulator includes a pulse generatorconfigured to deliver electrical therapeutic stimulation tuned torestore autonomic balance through continuously-cycling, intermittent andperiodic electrical pulses simultaneously delivered at an intensity thatavoids acute physiological side effects and with an unchanging cycle nottriggered by physiological markers in a manner that results in creationand propagation (in both afferent and efferent directions) of actionpotentials within neuronal fibers comprising a cervical vagus nerve of apatient through a pair of helical electrodes via an electrically couplednerve stimulation therapy lead. The neurostimulator also includes arecordable memory storing an autotitration operating mode that includesa maximum stimulation intensity and that is configured to perform astimulation autotitration following at least one of theneurostimulator's implantation into the patient and a disruption of thedelivery of the electrical therapeutic stimulation caused by a depletionof the neuro stimulator's power, the autotitration including an increasein intensity of the delivered electrical therapeutic stimulation, to alevel not exceeding the maximum stimulation intensity, performed uponreceipt of the unique signal associated with the up-titration command.The neurostimulator further includes an energy receiver configured totranscutaneously receive energy and recharge the rechargeable batterywith the received energy.

By restoring autonomic balance, therapeutic VNS operates acutely todecrease heart rate, increase heart rate variability and coronary flow,reduce cardiac workload through vasodilation, and improve leftventricular relaxation. Over the long term, VNS provides the chronicbenefits of decreased negative cytokine production, increased baroreflexsensitivity, increased respiratory gas exchange efficiency, favorablegene expression, renin-angiotensin-aldosterone system down-regulation,and anti-arrhythmic, anti-apoptotic, and ectopy-reducinganti-inflammatory effects. Furthermore, patient-controlled autotitrationof VNS stimulation allows the patient to avoid the unnecessary delaysassociated with visiting a physician's office for every step in thetitration to take place. Furthermore, providing the neurostimulator witha rechargeable battery allows to lessen the frequency of a disruption intherapy and the associated need to retitrate the therapy following areplacement of a neurostimulator with a depleted battery.

Still other embodiments of the present invention will become readilyapparent to those skilled in the art from the following detaileddescription, wherein are described embodiments by way of illustratingthe best mode contemplated for carrying out the invention. As will berealized, the invention is capable of other and different embodimentsand its several details are capable of modifications in various obviousrespects, all without departing from the spirit and the scope of thepresent invention. Accordingly, the drawings and detailed descriptionare to be regarded as illustrative in nature and not as restrictive.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a front anatomical diagram showing, by way of example,placement of an implantable vagus stimulation device in a male patient,in accordance with one embodiment.

FIGS. 2A and 2B are diagrams respectively showing the rechargeableimplantable neurostimulator for treatment of chronic cardiac dysfunctionand the simulation therapy lead of FIG. 1.

FIG. 3 is a diagram showing the charging components of the implantableneurostimulator of FIG. 1.

FIG. 4 is a diagram showing an external charger for use with theimplantable neurostimulator of FIG. 1.

FIG. 5 is a graph showing, by way of example, the relationship betweenthe targeted therapeutic efficacy and the extent of potential sideeffects resulting from use of the implantable neurostimulator of FIG. 1.

FIG. 6 is a timing diagram showing, by way of example, a stimulationcycle and an inhibition cycle of VNS as provided by implantableneurostimulator of FIG. 1.

FIG. 7 is a flow diagram showing an implantableneurostimulator-implemented method for treatment of chronic cardiacdysfunction with bounded titration in accordance with one embodiment.

FIG. 8 is a flow diagram showing a routine for adjusting intensity ofVNS therapy during autotitration based on patient feedback for themethod of FIG. 7.

DETAILED DESCRIPTION

Changes in autonomic control of the cardiovascular systems of patientssuffering from CHF and other cardiovascular diseases push the autonomicnervous system out of balance and favor increased sympathetic anddecreased parasympathetic central outflow. The imbalance is accompaniedby pronounced elevation of basal heart rate arising from chronicsympathetic hyperactivation along the neurocardiac axis. Medicallyunnecessary delays in providing CHF therapy to a patient can furtherdeteriorate the patient's health.

Low intensity peripheral neurostimulation therapies that target theimbalance of the autonomic nervous system have been shown to improveclinical outcomes in patients treated for three to twelve months.Bi-directional autonomic regulation therapy results in simultaneouscreation and propagation of efferent and afferent action potentialswithin the vagus nerve. In contrast to conventional approaches to VNS,the neurostimulation is delivered bi-directionally and at an intensitythat is insufficient to elicit pathological or acute physiological sideeffects, such as acute cardiac arrhythmias, and without the requirementof an enabling physiological feature or triggering physiological marker,such as heart rate or heart rate variability (HRV), such as for purposesof timing stimulation delivery, to confirm therapeutic effect, or otherends. Here, upon continuously-cycling, intermittent and periodic lowintensity stimulation of the cervical vagus nerve, action potentialspropagate away from the stimulation site in two directions, efferentlytoward the heart to influence the intrinsic cardiac nervous system andthe heart and afferently toward the brain to influence central elementsof the nervous system.

An implantable vagus nerve stimulator (neurostimulator), such as used totreat drug-refractory epilepsy and depression, can be adapted for use inmanaging chronic cardiac dysfunction through therapeutic bi-directionalvagal stimulation. While the VNS therapy may not be deliveredimmediately at a full therapeutic intensity, allowing the patient tocontrol the titration of intensity of VNS stimulation delivered to thepatient makes this titration process (“autotitration”) significantlyfaster when compared to a titration entirely controlled by a physician.In particular, the intensity of VNS delivered by the neurostimulator canbe adjusted by a patient-operable external controller, which allows thepatient to up-titrate the VNS within bounds set by in advance by aphysician or another healthcare professional. Thus, by allowing thepatient to perform up-titration of VNS intensity, the number of visitsto a physician's office is reduced, which in turn reduces the length ofthe titration process. Furthermore, the neurostimulator can also beinductively charged in situ to counter battery depletion duringoperation, and preventing the need to perform an additional cycle oftitration necessary when the neurostimulator is surgically replaced dueto a depleted battery. FIG. 1 is a front anatomical diagram showing, byway of example, placement of an implantable vagus nerve stimulation(VNS) device 11 in a male patient 10, in accordance with one embodiment.The VNS provided through the stimulation device 11 operates underseveral mechanisms of action. These mechanisms include increasingparasympathetic outflow and inhibiting sympathetic effects by blockingnorepinephrine release. More importantly, VNS triggers the release ofacetylcholine (ACh) into the synaptic cleft, which has beneficialanti-arrhythmic, anti-apoptotic, and ectopy-reducing anti-inflammatoryeffects.

The implantable vagus stimulation device 11 includes at least threeimplanted components, an implantable neurostimulator 12, a therapy lead13, and helical electrodes 14. The implantable vagus stimulation device11 can be remotely accessed following implantation through an externalprogrammer (not shown) and patient-operable external controller (notshown). For example, the implantable vagus stimulation device 11 can beremotely accessed following implantation through the external programmerby which the neurostimulator 12 can be remotely checked and programmed.In particular, the external programmer can be used to set parameters fordelivering VNS stimulation, such as duty cycle, output current(amplitude), frequency, and pulse width, with these parameters definingthe intensity at which VNS is delivered. For example, the externalprogrammer can be used to program a set of maximum stimulationparameters of VNS therapy that the neurostimulator 12 can deliver underany operating mode. For a commercial device sold by Cyberonics, Inc.,Houston, Tex., such parameters could be an output current of 3.5 MA,signal frequency of 30 Hz, and pulse width of 1000 μsec. Otherparameters are possible.

The external programmer can also be used by a healthcare professional tostore into the neurostimulator 12 an autotitration operating mode,described in detail infra with reference to FIGS. 7 and 8, which directsdelivery of VNS during the autotitration process under a control of apatient-operable external controller. The autotitration operating modeincludes limits, or boundaries, of the patient-controlled autotitration.For example, the autotitration operating mode can include a set of oneor more maximum stimulation parameters defining the maximum stimulationintensity of VNS therapy that the neurostimulator can deliver during theautotitration process; this limit prevents the patient 10 fromautotitrating above the maximum stimulation intensity. Once the maximumstimulation intensity is achieved during the autotitration process,further up-titration is prevented, and the patient 10 needs to visit ahealthcare professional's office, where the healthcare professional canuse the external programmer to program into the neurostimulator 12 anupdated set of maximum stimulation parameters. Other limitations can beincluded in the operating mode. For example, a patient 10 may be limitedto performing autotitration according to a predefined schedule, with thepermissible frequency of patient-controlled increases in intensity andthe period of time during which the patient can perform theautotitration being programmed into the operating mode. Other limits arepossible. As described further infra, with reference to FIGS. 7 and 8,the autotitration operating mode further defines the increments at whichthe stimulation parameters are increased during the autotitration aswell as the adjustments of the stimulation parameters that occur if thepatient 10 indicates that an increased level of stimulation is nottolerable. Other aspects of the autotitration process can be addressedby the operating mode.

A patient-operable external controller (not shown) allows the patient tocontrol the autotitration process, subject to the limits set by thehealthcare professional in the autotitration operating mode. Thepatient-operable external controller is configured to control theneurostimulator 12 by transmitting to the neurostimulator 12 uniquesignals associated with commands, such as a command to increase(up-titrate) intensity of VNS stimulation, or patient feedback regardingwhether an increased intensity of VNS therapy is tolerable. Thepatient-operable external controller can also suspend indefinitely VNSstimulation by supplying a magnetic signal to the neurostimulator, asfurther described in detail in the commonly-assigned U.S. patentapplication, “Vagus Nerve Neurostimulator With MultiplePatient-Selectable Modes For Treating Chronic Cardiac Dysfunction,” Ser.No. 13/352,244, filed on Jan. 17, 2012, now U.S. patent. Otherfunctionality of the patient-operable external controller is possible,as described in U.S. Pat. No. 8,571,654 cited supra.

In one embodiment, the patient-operable external controller can be anexternal magnet, such as described in commonly-assigned U.S. Pat. No.8,600,505, issued Dec. 3, 2013, entitled “Implantable Device ForFacilitating Control Of Electrical Stimulation Of Cervical Vagus NervesFor Treatment Of Chronic Cardiac Dysfunction,” the disclosure of whichis incorporated by reference. In a further embodiment, thepatient-operable external controller can be an external electromagneticcontroller, such as described in U.S. Pat. No. 8,571,654 cited supra.Other types of patient-operable external controllers are possible.Together, the implantable vagus stimulation device 11, the externalprogrammer, and one or more of the external controllers described abovecan form a VNS therapeutic delivery system.

The neurostimulator 12 is implanted in the patient's right or leftpectoral region generally on the same side (ipsilateral) as the cervicalvagus nerve 15, 16 to be stimulated, although otherneurostimulator-vagus nerve configurations, including contra-lateral andbi-lateral, are possible. The helical electrodes 14 are generallyimplanted on the vagus nerve 15, 16 about halfway between the clavicle19 a-b and the mastoid process. The therapy lead 13 and helicalelectrodes 14 are implanted by first exposing the carotid sheath andchosen vagus nerve 15, 16 through a latero-cervical incision on theipsilateral side of the patient's neck 18. The helical electrodes 14 arethen placed onto the exposed nerve sheath and tethered. A subcutaneoustunnel is formed between the respective implantation sites of theneurostimulator 12 and helical electrodes 14, through which the therapylead 13 is guided to the neurostimulator 12 and securely connected.

The stimulation device 11 bi-directionally stimulates the vagus nerve15, 16 through multimodal application of continuously-cycling,intermittent and periodic electrical stimuli, which are parametricallydefined through stored stimulation parameters and timing cyclesaccording to various operating modes. While the autotitration operatingmode described infra with reference to FIGS. 7 and 8 allows titration ofVNS intensity under a control of a patient-operable external controller,other operating modes can be implemented by the stimulation device 11.For example, in further embodiments, tachycardia and bradycardia inVNS-titrated patients can be respectively managed, such as described incommonly-assigned U.S. patent application Ser. No. 13/673,766, filed onNov. 9, 2012, entitled “Implantable Neurostimulator-Implemented Methodfor Managing Tachyarrhythmia Through Vagus Nerve Stimulation,” publishedas U.S. Patent Application Publication No. 2014/0135862 A1, pending, andU.S. Pat. No. 8,688,212, issued Apr. 1, 2014, entitled “ImplantableNeurostimulator-Implemented Method for Managing Bradycardia throughVagus Nerve Stimulation,” the disclosures of which are incorporated byreference. In a still further embodiment, prolonged activation of thesympathetic nervous system during post-exercise recovery periods,particularly in patients with CCD, can be managed through application ofa “boost” dose of VNS, such as described in commonly-assigned U.S.patent application Ser. No. 13/673,795, filed on Nov. 9, 2012, entitled“Implantable Neurostimulator-Implemented Method for EnhancingPost-Exercise Recovery through Vagus Nerve Stimulation,” published asU.S. Patent Application Publication No. 2014/0135863 A1, pending, thedisclosure of which is incorporated by reference.

Both sympathetic and parasympathetic nerve fibers are stimulated.Cervical vagus nerve stimulation results in the creation and propagationof action potentials (in both afferent and efferent directions) withinneuronal fibers comprising the cervical vagus nerve from the site ofstimulation to restore cardiac autonomic balance. Afferent actionpotentials propagate toward the parasympathetic nervous system's originin the medulla in the nucleus ambiguus, nucleus tractus solitarius, andthe dorsal motor nucleus, as well as towards the sympathetic nervoussystem's origin in the intermediolateral cell column of the spinal cord.Efferent action potentials propagate toward the heart 17 to activate thecomponents of the heart's intrinsic nervous system. The helicalelectrodes 14 can be implanted on either the left or right vaguscervical nerve 15, 16. The right vagus nerve 16 has a moderately lowerstimulation threshold than the left vagus nerve 15 for heart rateaffects at the same parametric levels of VNS.

The VNS therapy is delivered autonomously to the patient's vagus nerve15, 16 through three implanted components that include a neurostimulator12, therapy lead 13, and helical electrodes 14. FIGS. 2A and 2B arediagrams respectively showing the implantable neurostimulator 12 and thestimulation therapy lead 13 of FIG. 1. In one embodiment, theneurostimulator 12 can be adapted from a VNS Therapy AspireSR Model 105or Model 106 pulse generator, manufactured and sold by Cyberonics, Inc.,Houston, Tex., although other manufactures and types of single-pinreceptacle implantable VNS neurostimulators with or without integratedleadless heart rate sensors could also be used. The stimulation therapylead 13 and helical electrodes 14 are generally fabricated as a combinedassembly and can be adapted from a Model 302 lead, PerenniaDURA Model303 lead, or PerenniaFLEX Model 304 lead, also manufactured and sold byCyberonics, Inc., in two sizes based on helical electrode innerdiameter, although other manufactures and types of single-pinreceptacle-compatible therapy leads and electrodes could also be used.

Referring first to FIG. 2A, the neurostimulator 12 provides multimodalvagal stimulation. The neurostimulator 12 includes an electrical pulsegenerator that is tuned to restore autonomic balance by triggeringaction potentials that propagate bi-directionally (both afferently andefferently) within the vagus nerve 15, 16. The neurostimulator 12includes an electrical pulse generator that is tuned to restoreautonomic balance by triggering the creation of action potentials thatpropagate both afferently and efferently within the vagus nerve 15, 16.The neurostimulator 12 is enclosed in a hermetically sealed housing 21constructed of a biocompatible, implantation-safe material, such astitanium. The housing 21 contains electronic circuitry 22 powered by aprimary rechargeable battery 23, which can be a lithium-ion battery,such as lithium nickel manganese cobalt oxide. The electronic circuitry22 is implemented using complementary metal oxide semiconductor (CMOS)integrated circuits that include a microprocessor controller thatexecutes a control program according to stored stimulation parametersand timing cycles; a voltage regulator that regulates system power;logic and control circuitry, including a recordable memory 29 within theoperating modes and stimulation parameters are stored, that controlsoverall pulse generator function, receives and implements programmingcommands from the external programmer, or other external source,collects and stores telemetry information, processes sensory input, andcontrols scheduled and sensory-based therapy outputs; a transceiver thatremotely communicates with the external programmer using radio frequencysignals; an antenna, which receives programming instructions andtransmits the telemetry information to the external programmer; and areed switch 30 that provides remote access to the operation of theneurostimulator 12 using the external programmer or the patient-operableexternal controller. The recordable memory 29 can include both volatile(dynamic) and persistent (static) forms of memory, such as firmwarewithin which the stimulation parameters and timing cycles can be stored.Other electronic circuitry and components are possible.

Power supplied to the neurostimulator 12 is provided by the rechargeablebattery 23, which can be inductively charged by the patient 10 orcaregiver as necessary to replenish the battery 23. Recharging thebattery 23 allows delaying the disruption in delivery of VNS therapycaused by a depletion of the neurostimulator's 12 power, neurostimulator12 explantation, and a subsequent need to perform another round of VNStitration. FIG. 3 is a diagram showing the charging components of theimplantable neurostimulator 12 of FIG. 1. The rechargeable battery 23 ischargeable via inductive transcutaneous energy transfer. Anelectromagnetic coil 41 necessary to convert AC power into DC power,such as described in U.S. Pat. No. 5,350,413, issued Sep. 27, 1994 toMiller, the disclosure of which is incorporated by reference, isintegrated into the housing 21 of the neurostimulator 12. In addition,charging circuitry 42 is coupled with the electromagnetic coil 41 andthe rechargeable battery 23.

During charging, the patient 10 or other caregiver places an inductivecharging wand over the implantation site of the neurostimulator 12. FIG.4 is a diagram showing an external charger 50 for use with theimplantable neurostimulator 12 of FIG. 1. The external charger 50includes an inductive charging wand 51 that sends energy to theelectromagnetic coil 14 through a transcutaneous inductive coupling, andthe charging circuitry 42 converts the energy back into electricalcurrent, which charges the onboard rechargeable battery 23. Theinductive charging wand 51 encloses an inductive charging coil (notshown) on a distal end, which is placed over the implantation site ofthe neurostimulator 12. The inductive charging wand 51 is plugged into awall outlet or other electrical power source with a power cord 54 orsimilar type of connector. Once placed over the implantation site, thepatient 10 or caregiver presses a button 52 or other patient-operablecontrol to start the charging of the neurostimulator 12.

The respective electromagnetic coils in the neurostimulator 12 and theinductive charging wand 51 form a transcutaneous inductive coupling whenthe button 52 is pressed, during which time alternating current energyis transferred into the neurostimulator 12, converted back intoelectrical current, and used to charge the rechargeable battery 23.Other ways for the neurostimulator 12 to transcutaneously receive energyfrom an external charging source are possible. For example, theneurostimulator 12 can include at least one photovoltaic cell, such asdescribed in U.S. Patent Publication No. 2009/0326597, published Dec.31, 2009, abandoned, the disclosure of which is incorporated byreference. In one embodiment, the photovoltaic cell is subcutaneouslyplaced away from the housing 21 of the neurostimulator 12. Thephotovoltaic cell is electrically interfaced with the charging circuitry42 via electrical wiring. The photovoltaic cell absorbs light passingthrough the patient's translucent layers of skin, and converts the lightinto electrical energy, which is then fed through the charging circuitry42 into the rechargeable battery 23. The photovoltaic cell can absorbeither the light naturally coming from the patient's surroundings, orlight generated by an energy generator containing a light source, suchas described in U.S. Pat. No. 6,961,619, issued Nov. 1, 2005, to Casey,the disclosure of which is incorporated by reference. In one embodiment,the energy generator is placed against the patient's skin in alignmentwith the location of the photovoltaic cell. Still other ways totranscutaneously transmit energy are possible.

Ordinarily, the charging circuitry 42 charges the rechargeable battery23, but prevents overcharging beyond the limits of the battery. In afurther embodiment, the charging circuitry 42 measures the rechargeablebattery's state of charge for reporting status to the patient 10 orcaregiver. The charging circuitry 42 is electrically interfaced with themicroprocessor controller, and provides the state of charge of therechargeable battery 23. The neurostimulator 12 can provide feedbackconcerning the state of charge by transmitting status information to theexternal programmer or another remotely-interfaceable interrogationdevice using a transceiver and the antenna, either at the request of theexternal programmer or when the state of charge reaches a predeterminedlevel. The external programmer can be the programming wand, as describedinfra, or be included as part of the charging circuitry 42. In a furtherembodiment, the neurostimulator can transmit status information to thepatient-operable external controller. Other ways of interacting with thecharging circuitry 42 are possible.

Referring back to FIG. 2A, the neurostimulator 12 externally includes aheader 24 to securely receive and connect to the therapy lead 13. In oneembodiment, the header 24 encloses a receptacle 25 into which a singlepin for the therapy lead 13 can be received, although two or morereceptacles could also be provided, along with the requisite additionalelectronic circuitry 22. The header 24 internally includes a leadconnector block (not shown) and a set of set screws 26.

In one embodiment, the housing 21 can also contain a heart rate sensor31 that is electrically interfaced with the logic and control circuitry,which receives the patient's sensed heart rate or, alternatively, HRV,as sensory inputs. In a further embodiment, the heart rate sensor 31 iseither external to or physically separate from the neurostimulator 12proper, but is operatively coupled, either through physical wiredconnection or via wireless interface. The heart rate sensor 31 monitorsheart rate or HRV using an ECG-type electrode. Through the electrode,the patient's heart beat can be sensed by detecting ventriculardepolarization or similar physiology. In a further embodiment, aplurality of electrodes can be used to sense voltage differentialsbetween electrode pairs, which can undergo signal processing for furthercardiac physiological measures, for instance, detection of the P-wave,QRS complex, and T-wave. The heart rate sensor 31 provides the sensedheart rate or HRV to the control and logic circuitry as sensory inputsthat can be used to determine the presence of arrhythmias, especiallyVT.

As mentioned above, the neurostimulator 12 can be interrogatedpreferably prior to implantation and throughout the therapeutic periodwith a healthcare provider-operable external programmer and programmingwand (not shown) for checking proper operation, downloading recordeddata, diagnosing problems, and programming operational parameters andoperating modes, such as described in commonly-assigned U.S. Pat. No.8,600,505, issued Dec. 3, 2013, and U.S. Pat. No. 8,571,654, citedsupra. In particular, the neurostimulator 12 is interrogated prior tostarting of titration of VNS therapy. In one embodiment, the externalprogrammer executes application software specifically designed tointerrogate the neurostimulator 12. The programming computer interfacesto the programming wand through a standardized wired or wireless dataconnection. The programming wand can be adapted from a Model 201Programming Wand, manufactured and sold by Cyberonics, Inc. and theapplication software can be adapted from the Model 250 ProgrammingSoftware suite, licensed by Cyberonics, Inc. Other configurations andcombinations of external programmer, programming wand and applicationsoftware are possible.

The neurostimulator 12 delivers VNS under control of the electroniccircuitry 22. The stored stimulation parameters are programmable. Eachstimulation parameter can be independently programmed to define thecharacteristics of the cycles of therapeutic stimulation and inhibitionto ensure optimal stimulation for a patient 10. The programmablestimulation parameters include output current, signal frequency, pulsewidth, signal ON time, signal OFF time, magnet activation (for VNSspecifically triggered by a magnetic signal, such as during theautotitration process in one embodiment), and reset parameters. Otherprogrammable parameters are possible. In addition, sets or “profiles” ofpre-selected stimulation parameters can be provided to physicians withthe external programmer and fine-tuned to a patient's physiologicalrequirements prior to being programmed into the neurostimulator 12, suchas described in commonly-assigned U.S. Pat. No. 8,630,709, issued Jan.14, 2014, entitled “Computer-Implemented System and Method for SelectingTherapy Profiles of Electrical Stimulation of Cervical Vagus Nerves forTreatment of Chronic Cardiac Dysfunction,” the disclosure of which isincorporated by reference. In a further embodiment, sets or “profiles”of pre-selected stimulation parameters can be provided to physicians,which can be selected with the assistance of an external programmer andfine-tuned to a patient's physiological requirements prior to beingprogrammed into the neurostimulator 12 following implantation.

Referring next to FIG. 2B, the therapy lead 13 delivers an electricalsignal from the neurostimulator 12 to the vagus nerve 15, 16 via thehelical electrodes 14. On a proximal end, the therapy lead 13 has a leadconnector 27 that transitions an insulated electrical lead body to ametal connector pin 28. During implantation, the connector pin 28 isguided through the receptacle 25 into the header 24 and securelyfastened in place using the set screws 26 to electrically couple thetherapy lead 13 to the neurostimulator 12. On a distal end, the therapylead 13 terminates with the helical electrode 14, which bifurcates intoanodic and cathodic electrodes. In one embodiment, the lead connector 27is manufactured using silicone and the connector pin 28 is made ofstainless steel, although other suitable materials could be used, aswell. The insulated lead body 13 utilizes a silicone-insulated alloyconductor material.

Preferably, the helical electrodes 14 are placed over the cervical vagusnerve 15, 16 at the location below where the superior and inferiorcardiac branches separate from the cervical vagus nerve. In alternativeembodiments, the helical electrodes may be placed at a location abovewhere one or both of the superior and inferior cardiac branches separatefrom the cervical vagus nerve. In one embodiment, the helical electrodes14 are positioned around the patient's vagus nerve oriented with the endof the helical electrodes 14 facing the patient's head. In an alternateembodiment, the helical electrodes 14 are positioned around thepatient's vagus nerve 15, 16 oriented with the end of the helicalelectrodes 14 facing the patient's heart 17. At the distal end, theinsulated electrical lead body 13 is bifurcated into a pair of leadbodies that are connected to a pair of electrodes proper. The polarityof the electrodes could be configured into a monopolar cathode, aproximal anode and a distal cathode, or a proximal cathode and a distalanode.

The VNS is delivered as a multimodal set of therapeutic and event-baseddoses, which are system output behaviors that are pre-specified withinthe neurostimulator 12 through the stored stimulation parameters andtiming cycles implemented in firmware programming and executed by themicroprocessor controller. The selections of therapeutic dose and dutycycle are a tradeoff among competing medical considerations. FIG. 5 is agraph 60 showing, by way of example, the relationship between thetargeted therapeutic efficacy 63 and the extent of potential sideeffects 64 resulting from use of the implantable neurostimulator 12 ofFIG. 1. The x-axis represents the duty cycle 61. The y-axis representsrelative quantified physiological response 62 to VNS therapy. Theneurostimulation is delivered bi-directionally and at an intensity thatis insufficient to elicit pathological or acute physiological sideeffects, such as acute cardiac arrhythmias, and without the requirementof an enabling physiological feature or triggering physiological marker,such as heart rate or HRV.

The duty cycle 61 is determined by dividing the stimulation ON time bythe sum of the ON and OFF times of the neurostimulator 12 during asingle ON-OFF cycle. In a further embodiment, the stimulation time caninclude ramp-up and ramp-down times respectively preceding and followingthe ON time during which the neurostimulator 12 delivers the VNS at fulloutput current, such as further described infra with reference to FIG.6. Ramp-up and ramp-down times may be necessary, for instance, when thestimulation frequency exceeds a minimum threshold. The physiologicalresponse 62 can be expressed quantitatively for a given duty cycle 61 asa function of the targeted therapeutic efficacy 63 and the extent ofpotential side effects 64. The maximum level (“max”) 66 of physiologicalresponse 62 signifies the highest point of targeted therapeutic efficacy63 or potential side effects 64.

The therapeutic efficacy 63 represents the intended effectiveness of VNSin provoking a beneficial physiological response, which may be patient-or population-dependent. In contrast to conventional feedback-driven VNSapproaches that require an enabling physiological feature to gaugestimuli delivery efficacy, the acute responses and chronic contributingfactors need not be (and are likely not) directly observedcontemporaneous to VNS delivery. Rather, the contributing factors couldbe clinically measured over time, such as in-clinic during patientfollow up via ECG trace or other metric. As well, in on-going laboratorystudies involving canines, increased heart beat regularity during VNS ontime, as exhibited through decreased heart rate variability, has beencreditably detected through 24-hour Holter monitoring during vagalneural stimulation at a constant continuously-cycling level below asubcardiac threshold, above which there is a slowing of heart rate,conduction velocity or other cardiac artifact.

The therapeutic efficacy 63 can be quantified by assigning values to therealized acute and chronic responses, which together contribute to andsynergistically produce the beneficial physiological response. Acuteresponses include realized changes in HRV, increased coronary flow,reduction in cardiac workload through vasodilation, and improvement inleft ventricular relaxation. Chronic factors include improvedcardiovascular regulatory function, decreased negative cytokineproduction, increased baroreflex sensitivity, increased respiratory gasexchange efficiency, favorable gene expression,renin-angiotensin-aldosterone system down-regulation, anti-arrhythmic,anti-apoptotic, and ectopy-reducing anti-inflammatory effects. Stillother acute responses and chronic factors are possible.

Beneficial physiological response is generally also considered to bepatient dependent, whereby certain of the contributing factors may bemore important for one patient as compared to other patients, and nosingle contributing factor is fully dispositive or conclusive of whetherthe physiological response is beneficial for any given patient. Thecontributing factors can be combined in any manner to quantify therelative level of therapeutic efficacy 63, including weightingparticular factors more heavily than others, by tailoring the importanceof each contributing factor on a patient-specific or population-specificmanner, or applying statistical or numeric functions based directly onor derived from realized changes to the patient's physiology. Forexample, therapeutic goals of achieving an increase of HRV of 10% anddecreased negative cytokine production of 3% may be desired for aparticular patient with equal weight assigned to each of these goals.Maximum physiological response 66 occurs when these goals aresubstantially met.

Empirically, therapeutic efficacy 63 steeply increases beginning ataround a 5% duty cycle (patient-dependent), as beneficial physiologicalresponse 62 is realized, and levels off in a plateau near the maximumlevel 66 of physiological response 62 at around a 30% duty cycle(patient-dependent), although some patients may require higher (orlower) duty cycles to show similar beneficial physiological response 62.Thereafter, therapeutic efficacy 63 begins decreasing at around a 50%duty cycle (patient-dependent) and continues in a plateau near a 25%physiological response (patient-dependent) through the maximum 100% dutycycle.

The physiological response and occurrence of side effects to differentcombinations of VNS parameters and timing cycles has been empiricallyevaluated in pre-clinical work on canines Like the therapeutic efficacy63, side effects 64 may be patient- or population-dependent and can bequantified by assigning values to the realized acute and chronic sideeffects. For example, benign acute side effects, such as coughing, couldbe assigned a low value, while pathological side effects, likebradycardia, could be rated significantly higher to reflect level ofseverity. In the canine study, the only side effects that were observedwere coughing and throat irritation, retching, and bradycardia during4-6 weeks of gradual titration. Following titration, the only remainingside effect that was observed was bradycardia, which was observed in thefollowing ranges:

Right VNS: In an awake animal, bradycardia was typically observedbeginning at approximately 1.25-1.5 mA at a pulse width of 500 μsec andapproximately 1.5-1.75 mA at a pulse width 250 μsec, independent ofstimulation frequency. However, the magnitude of the current-dependentbradycardia increased with stimulation frequency, with the highest levelof bradycardia observed at 20 Hz, the lowest level observed at 10 Hz,and an intermediate level observed at 15 Hz. During sleep, bradycardiawas observed at similar parameters as in an awake animal.

Left VNS: In an awake animal, bradycardia was only observed atamplitudes greater than 2.5 mA, and primarily in the 3.0-3.5 mA range.Stimulation frequencies of 15 or 20 Hz were more likely to producebradycardia at the lower end of that amplitude range, and a stimulationfrequency of 10 Hz was more likely to produce bradycardia only at theupper end of the range. In some animals, no bradycardia was observed atany combination of parameters up to the maximum stimulation current of3.5 mA. During sleep, bradycardia was observed at similar parameters asin an awake animal. Comparable ranges of side effects in humans areexpected.

In the absence of patient physiology of possible medical concern, suchas acute cardiac arrhythmias, VNS is delivered in therapeutic doses thateach use alternating cycles of stimuli application (ON) and stimuliinhibition (OFF) that are tuned to activate both afferent and efferentpathways. Stimulation results in parasympathetic activation andsympathetic inhibition, both through centrally-mediated pathways andthrough efferent activation of preganglionic neurons and local circuitneurons. FIG. 6 is a timing diagram showing, by way of example, astimulation cycle and an inhibition cycle of VNS 70 as provided byimplantable neurostimulator 12 of FIG. 1. The stimulation parametersenable the electrical stimulation pulse output by the neurostimulator 12to be varied by both amplitude (output current 66) and duration (pulsewidth 64). The set of stimulation parameters and timing cycle useddepends upon the operating mode of therapy desired, which in thedescribed embodiment is the titration mode further described below withreference to FIGS. 7 and 8. Other modes are possible. The number ofoutput pulses delivered per second determines the signal frequency 63.In one embodiment, a pulse width in the range of 100 to 250 μsec is usedto deliver between 0.1 and 10 mA of output current at a signal frequencyof 5 to 20 Hz, although other therapeutic values could be used asappropriate.

In the simplest case, the stimulation time equals the time period duringwhich the neurostimulator 12 is ON and delivering pulses of stimulation.The OFF time 75 equals the time period occurring in-between stimulationtimes 71 during which the neurostimulator 12 is OFF and inhibited fromdelivering stimulation. In one embodiment, the neurostimulator 12implements either or both of a ramp-up time 77 and a ramp-down time 78that respectively precede and follow the ON time 72 during which theneurostimulator 12 is ON and delivering pulses of stimulation at thefull output current 76. The ramp-up time 77 and ramp-down time 78 areused when the stimulation frequency is at least 10 Hz, although otherminimum thresholds could be used, and both ramp-up and ramp-down times77, 78 last two seconds, although other time periods could also be used.The ramp-up time 77 and ramp-down time 78 allow the strength of theoutput current 76 of each output pulse to be gradually increased anddecreased, thereby avoiding deleterious reflex behavior due to suddendelivery or inhibition of stimulation at a full-strength programmedlevel of intensity.

As described above, titrating VNS stimulation by having a physicianperform each step in the titration creates a medically unnecessary delayin delivering VNS at a full therapeutic intensity to the patient 10. Onthe other hand, allowing a patient 10 to autotitrate the VNS intensitywithout physician oversight creates a safety concern. A patient maytitrate more aggressively than the physician would like, or mayexperience painful stimulation if the titration is not performedcorrectly. Allowing the patient 10 to titrate the VNS stimulationsubject to limits set by the patient's physician allows both to avoidthe delays associated with visiting the physician's office and tomitigate the safety issues associated with an unsupervisedautotitration. FIG. 7 is a flow diagram showing an implantableneurostimulator-implemented method 80 for treatment of chronic cardiacdysfunction with bounded titration in accordance with one embodiment.Initially, after a patient 10 recovers from the implantation of theneurostimulator, a healthcare professional programs the neurostimulator12 using the external programmer and stores the autotitration operatingmode into the recordable memory 29 of the neurostimulator (step 81). Asmentioned supra, the operating mode includes one or more parametersdefining the highest-intensity dose of VNS stimulation that the patient10 can command the neurostimulator 12 to deliver during theautotitration process (“maximum stimulation intensity”). This maximumstimulation intensity can be defined either through a single parameter,such as the output current, or through a combination of parameters, withthe parameters defining the maximum charge delivered. The autotitrationoperating mode can include other limitations on the autotirationprocess, such as a predefined schedule according to which the patient 10can up-titrate the VNS stimulation. For example, the operating mode canspecify that the VNS therapy can be up-titrated once a week for a periodof thirty days. The autotitration operating mode can further specify aroutine for adjusting the level of VNS stimulation delivered based onthe feedback received from the patient 10 regarding whether theup-titrated VNS is tolerable, as further described with reference toFIG. 8. In addition, the operating mode includes the parameters definingan initial dose of VNS stimulation delivered at the start of theautotitration (“titration dose”). In one embodiment, the parameters ofthe titration dose can be an output current of 0.25 mA, pulse width of250 μsec, signal frequency of 10 Hz, On time of 14 seconds, and Off timeof 1.1 minutes. The intensity of the titration dose is parametricallydefined to not exceed the maximum stimulation intensity, which includesthe titration dose having one or more of an output current lower orequal to the maximum stimulation intensity output current, a duty cyclelower or equal to the maximum stimulation intensity duty cycle, afrequency lower or equal to the maximum stimulation intensity frequency,and a pulse width shorter or equal to the maximum stimulation intensitypulse width. Finally, the autotitration operating mode is furtherconfigured to suspend VNS upon receiving an appropriate signal from theexternal controller.

Once the autotitration operating mode is received (step 91), theneurostimulator 12 starts therapeutically delivering the titration doseof VNS stimulation (step 82). When the patient 10 uses the externalcontroller to up-titrate the intensity, the neurostimulator 12 receivesfrom the external controller a unique signal, such as a magnetic signal,associated with the command to up-titrate the intensity of the titrationdose (step 83). For example, if the patient-operable external controlleris an external magnet, the signal can be a unique predefined patter ofswipes with the magnet performed by the patient 10 when the patientdesires to up-titrate the delivered VNS intensity. Similarly, if thepatient-operable external controller is an external electromagneticcontroller, such as described in U.S. Pat. No. 8,571,654 cited supra,the patient 10 can press an appropriately-labeled button on theelectromagnetic controller when the patient 10 desires to up-titrate theVNS therapy, with the electromagnetic controller sending to theneurostimulator a unique magnetic signal associated with the command toincrease the intensity of the titration dose.

Upon receipt of the signal (step 83), the neurostimulator 12 determineswhether further increasing the intensity at which the titration dose isdelivered would exceed the limits set down by the set down in theautotitration operating mode, and if the limits would be exceeded (step84), the therapeutic delivery of the titration dose continues at thesame intensity as before (step 85), ending the method 80. For example,if increasing the intensity of the titration dose would make thetitration dose intensity higher than the maximum intensity dose, thetitration dose intensity would not be increased, but would continue atthe same level. At that point, the only way for the intensity of thedelivered VNS therapy to be increased is for the patient to visit aphysician, who will reprogram the neurostimulator 12 with a set ofupdated limits. For example, if maximum intensity dose is initiallydefined as having an output current of 1.0 mA, upon autotitrating theintensity once a week for 4 weeks, the output current at which thetitration dose is delivered would reach 1.0 mA, requiring the patient tovisit the physician's office, where the physician would increase themaximum intensity to, for example, 2.0 mA. After this follow-up visit,the patient could continue autotitrating the VNS therapy until theupdated limits are reached.

Similarly, in a further embodiment, if the patient 10 attempts toincrease the intensity of the titration dose contrary to other limits,such contrary to the predefined schedule, the neurostimulator 12 willcontinue delivering the titration dose without increasing the intensity(step 85).

If at step 84 the intensity of the titration dose would not exceed thelimits, the intensity of the titration dose delivered to the patient isadjusted as specified in the autotitration operating mode (step 96),such as by increasing one or more parameters defining the titration doseintensity, as further described in detail with reference to FIG. 8. Thedelivery of the titration dose at the adjusted intensity continues perstep 82. While the embodiment described in reference to FIG. 8 describesthe autotitration being performed after an implantation (orre-implantation) of the neurostimulator 12, in a further embodiment, themethod 80 can be performed under other circumstances.

While physician-imposed limits on autotitration are instrumental inmitigating safety concerns, receiving patient feedback regarding whetheran increased intensity of stimulation is tolerable to the patient 10provides additional safeguards against a patient 10 autotitrating VNSstimulation overly aggressively. Furthermore, adjusting VNS intensitybased on the patient feedback presents an alternative to suspending VNSstimulation altogether upon the increased level of stimulation becomingintolerable, thus preserving the continuity of the titration. FIG. 8 isa flow diagram showing a routine 90 for adjusting intensity of VNStherapy during autotitration based on patient feedback for the method 80of FIG. 7. Continuing with the example of FIG. 8, the initial intensityof the titration dose can be defined using the following parameters: anoutput current of 0.25 mA, pulse width of 250 μsec, signal frequency of10 Hz, ON time of 14 seconds, and OFF time of 1.1 minutes. Once theneurostimulator 12 receives the unique signal from the patient-operableexternal controller associated with a command to up-titrate thetitration dose intensity, the neurostimulator 12 increases one of theparameters defining the titration dose intensity, with the titrationdose being continuously delivered upon the intensity being adjusted perstep 82 (step 91). In the described embodiment, the parameter increasedis output current (step 91), with the increase being 0.25 mA. Followingthe increase of the delivered intensity of the titration dose, theneurostimulator 12 receives feedback from the patient-operable externalcontroller regarding whether the increased intensity titration dose issubjectively tolerable to the patient 10 (step 92). The feedback isreceived as one or more unique signals from the controller, withdiffering signals indicating whether the increased intensity of thetitration dose is tolerable or not. For example, if the externalcontroller is an external magnet, the patient 10 can indicate whetherthe increased intensity is tolerable or not by performing differentpatterns of swipes with the magnet. Similarly, if the patient-operableexternal controller is an external electromagnetic controller, thecontroller can transmit unique magnetic signals to the neurostimulator12 that are associated with the increased intensity being tolerable orintolerable.

If the increased intensity is tolerable to the patient (step 93), theroutine 90 returns to step 91, and the output current of the deliveredtitration dose is further increased (step 91). If the increasedintensity is intolerable to the patient (step 103), the output currentis reverted to the level that the patient has indicated tolerable, or ifthe patient has not indicated a tolerable level, to the initial levelindicated in the autotitration operating mode (step 94). In the samestep, a different parameter of the delivered titration dose, such aspulse width, is increased, with the pulse width increasing to 500 μsecin the described embodiment (step 94). Patient feedback is receivedregarding whether the titration dose delivered at the increased pulsewidth is tolerable (step 95), and if the patient 10 indicates that thetitration dose at the increased pulse width is tolerable (step 96),another parameter, such as signal frequency, is also increased, with thefrequency being increased to 15 Hz in the described embodiment (step97). If the patient 10 indicates that titration dose delivered at theincreased pulse width is intolerable (step 96), the pulse width isreverted to the initial setting and another parameter, such as signalfrequency, is increased, with the signal frequency being increased to 15Hz in the described embodiment (98).

Upon the increase in signal frequency in steps 97 or 98, patientfeedback is received regarding whether the increase in frequency istolerable (step 99). If the delivery of the increase is not tolerable(step 100), the signal frequency is reverted back to the initial levelof 10 Hz (step 101), ending the routine 90. Until the next signalassociated with a command to up-titrate the VNS therapy is received fromthe external controller, the titration dose is delivered at theintensity indicated as tolerable by the patient, or if the patient 10has indicated that the increased intensity is not tolerable, at theinitial titration dose intensity. If the delivery of the titration doseat the increased signal frequency is tolerable (step 100), the frequencyis further increased to, in the described embodiment, 20 Hz (step 102).Patient feedback is once again received regarding whether the deliveryof the titration dose at the further increased signal frequency istolerable (step 103), and if the titration dose is tolerable (104), theroutine 90 terminates, with the neurostimulator 12 continuing to deliverthe increased titration dose per step 82 above. If the titration dosedelivered at the further increased signal frequency is not tolerable(step 104), the signal frequency is reverted to a level indicated by thepatient as tolerable (step 105), ending the routine. Other levels of theparameters can be used in the adjustment of the titration doseintensity. While the described embodiment, multiple parameters areadjusted, in a further embodiment, only a single parameter, such outputcurrent, can be adjusted in the routine 90. Furthermore, as describedsupra, at any moment in the routine 100, the patient 10 can indefinitelysuspend VNS therapy using the external controller.

While the invention has been particularly shown and described asreferenced to the embodiments thereof, those skilled in the art willunderstand that the foregoing and other changes in form and detail maybe made therein without departing from the spirit and scope.

What is claimed is:
 1. A vagus nerve neurostimulator for treatment ofchronic cardiac dysfunction, comprising: a pulse generator, wherein thepulse generator generates a pulsed electrical signal comprising: asignal ON time; a signal OFF time; an output current; a signalfrequency; a pulse width; and a duty cycle defined by dividing thesignal ON time by the sum of the signal ON time and signal OFF time; atherapy lead; an electrode communicatively coupled to the pulsegenerator via the therapy lead; and a recordable memory storing amaximum stimulation intensity and an autotitration operating modeconfigured to cause the pulse generator to increase an intensity of thepulsed electrical signal up to a level not exceeding the maximumstimulation intensity.
 2. The vagus nerve neurostimulator according toclaim 1, wherein the signal frequency comprises approximately 10 Hz. 3.The vagus nerve neurostimulator according to claim 1, wherein theautotitration mode is configured to cause the pulse generator to applythe pulsed electrical signal to a vagus nerve via the electrode topropagate action potentials in both afferent and efferent directionsalong the vagus nerve at an intensity that avoids acute physiologicalside effects.
 4. The vagus nerve neurostimulator according to claim 1,wherein the autotitration mode is configured to cause the pulsegenerator to increase the intensity of the delivered pulsed electricalsignal in association with receipt of a unique signal.
 5. The vagusnerve neurostimulator according to claim 4, wherein autotitration modeis further configured to receive a second unique signal indicating thatthe increased intensity of the delivered pulsed electrical signal is nottolerable to the patient.
 6. The vagus nerve neurostimulator accordingto claim 5, wherein the autotitration mode is further configured tocause the pulse generator to discontinue the increase in intensity uponreceipt of the second unique signal.
 7. The vagus nerve neurostimulatoraccording to claim 1, wherein the duty cycle comprises a value in arange of 5% to 20%.
 8. The vagus nerve neurostimulator according toclaim 1, wherein the pulse generator is configured to deliver the pulsedelectrical signal to a vagus nerve via the electrode to induce heartrate variability during the signal ON time.
 9. The vagus nerveneurostimulator according to claim 1, further comprising a sensorconfigured to monitor heart rate.
 10. The vagus nerve neurostimulatoraccording to claim 1, further comprising: a patient-operable externalcontroller configured to transmit a plurality of signals to the pulsegenerator including a unique signal associated with an up-titrationcommand; wherein the autotitration operating mode is further configuredto cause the pulse generator to continue delivery of the pulsedelectrical signal at the intensity up to the level not exceeding themaximum stimulation intensity regardless of receipt of the unique signalassociated with the up-titration command from the patient-operableexternal controller upon the intensity of the delivered electricaltherapeutic stimulation equaling the maximum stimulation intensity. 11.The vagus nerve neurostimulator according to claim 1, wherein theautotitration operating mode is configured to cause the pulse generatorto increase the intensity of the pulsed electrical signal upon receiptof a unique signal indicating that the current intensity of the pulsedelectrical signal is tolerable to the patient, and decrease theintensity upon receipt of a unique signal indicating that the currentintensity of the pulsed electrical signal is not tolerable to thepatient.
 12. A method of operating a vagus nerve neurostimulator totreat chronic cardiac dysfunction, comprising: delivering a pulsedelectrical signal to a vagus nerve via an electrode coupled to a pulsegenerator via a therapy lead, the pulsed electrical signal comprising: asignal ON time; a signal OFF time; an output current; a signalfrequency; a pulse width; and a duty cycle defined by dividing thesignal ON time by the sum of the signal ON time and signal OFF time; andoperating the pulse generator in an autotitration operating mode, theautotitration operating mode comprising increasing an intensity of thepulsed electrical signal up to a level not exceeding a maximumstimulation intensity stored in a recordable memory.
 13. The methodaccording to claim 12, wherein the signal frequency comprisesapproximately 10 Hz.
 14. The method according to claim 12, wherein thedelivering the pulsed electrical signal to the vagus nerve comprisesdelivering the pulsed electrical signal to the vagus nerve to propagateaction potentials in both afferent and efferent directions along thevagus nerve at an intensity that avoids acute physiological sideeffects.
 15. The method according to claim 12, wherein the operating thepulse generator in the autotitration operating mode comprises increasingthe intensity of the delivered pulsed electrical signal in associationwith receipt of a unique signal.
 16. The method according to claim 15,further comprising receiving a second unique signal indicating that theincreased intensity of the delivered pulsed electrical signal is nottolerable to the patient.
 17. The method according to claim 16, whereinthe autotitration mode is configured to discontinue the increase inintensity upon receipt of the second unique signal.
 18. The methodaccording to claim 12, wherein the duty cycle comprises a value in arange of 5% to 20%.
 19. The method according to claim 12, wherein thedelivering the pulsed electrical signal to the vagus nerve induces heartrate variability during the signal ON time.
 20. The method according toclaim 12, further comprising monitoring a patient heart rate.
 21. Themethod according to claim 12, further comprising: in response toreceiving from a patient-operable external controller a unique signalindicating that the current intensity of the pulsed electrical signal istolerable to the patient, increasing the intensity of the pulsedelectrical signal; and in response to receiving from thepatient-operable external controller a second unique signal indicatingthat the current intensity of the pulsed electrical signal is nottolerable to the patient, decreasing the intensity of the pulsedelectrical signal.
 22. The method according to claim 12, furthercomprising: continuing delivery of the pulsed electrical signal at theintensity up to the level not exceeding the maximum stimulationintensity regardless of receipt of a unique signal associated with anup-titration command from a patient-operable external controller uponthe intensity of the delivered electrical therapeutic stimulationequaling the maximum stimulation intensity.